April 3, 2011

March 31st, 2011 New data presented at the International Liver CongressTM today show the existence of novel interactions between T cells and hepatocytes that are regulated by HCV infection, providing a novel understanding of how HCV persists in the liver.

The nature of the T cell-hepatocyte interactions alter CD4+ T-cell trafficking and cytokine expression, and may have an impact on T-cell effector function and the outcome of anti-viral immune responses.

Innate and adaptive immune responses play a critical role in clearing acute HCV infection. Evidence from models suggest that CD4+ T cells play a critical role in controlling acute HCV infection, but the mechanism(s) behind their failure to control chronic HCV replication are still unknown.

The virus, which can go undetected for years, is the leading cause of liver failure in the United States, and for many patients, a transplant is the only life-saving treatment. But the hepatitis C virus circulates in the blood, and during transplant surgery, infected blood immediately gets into a donated liver.

“One-hundred percent (of transplanted livers) get re-infected,” said Dr. Donna M. Ambrosino, executive director of Massachusetts Biologic Laboratories, a division of the University of Massachusetts Medical School. “The virus stays in the blood for a couple of days, if not longer. You cannot be without your liver, and you can't put the new liver in without blood spilling on it and getting into it. So we're between a rock and a hard place.”

A re-infected liver, while giving patients perhaps five more years of life, she said, accelerates the course of the disease, and standard antiviral medications are not well-tolerated in transplant patients.

The medical school, along with five hospitals in Boston, New York and Connecticut, is entering the second phase of a clinical trial of a new treatment for the prevention of hepatitis C re-infection in liver transplant patients. The treatment, a monoclonal antibody, is different from the usual antiviral drugs in that it binds the virus and blocks its ability to get into the liver, Dr. Ambrosino said.

There are 10 patients currently in the study, with a target enrollment of 16 patients. Half are given the antibody, so far known only as MBL-HCV1, and half are given a placebo.

Dr. Ambrosino, who is also a professor of pediatrics at the medical school, said results will likely be available in the summer. If the virus is not found in patients 42 days after transplantation, it will be deemed a success. If the virus is found, a trial with a higher dose of antibody will begin.

The antibody — or the placebo — is administered to patients by infusion, in phases.

The first dose is given a few hours before transplant surgery, and another is given during surgery between when the diseased liver is removed and the donor liver is implanted. A third infusion is given just after surgery, followed by daily infusions during the first week of recovery. A final infusion is given on the 14th day after surgery.

A 2009 study of the antibody in 31 healthy volunteers showed no serious side effects.

Dr. Ambrosino said it generally takes 10 years of development and trials before a new medication becomes available.

According to the U.S. Centers for Disease Control and Prevention, hepatitis C virus infection is the most common chronic blood-borne infection in the United States, with approximately 3.2 million people chronically infected, and about 10,000 deaths per year. Of 6,000 or so liver transplants each year in the United States, half are the result of hepatitis C infection.

However, it is a slow-growing infection that may not show symptoms for 20 years — until liver failure becomes apparent, or abnormal laboratory tests are found.

Dr. Ambrosino said because the average age of a hepatitis C patient is 55 — smack in the middle of the baby boomer generation — they will probably make up the next wave of patients.

“So that's a large group, and there will be more people needing liver transplants,” she said.

While many boomers unknowingly carry the virus, Dr. Ambrosino said it is not entirely because of bad behavior such as drug use and multiple sex partners in the 1970s.

Hepatitis C can be transmitted through drug use via contaminated needles, and rarely through sexual contact, but she said the majority of cases were contracted through blood transfusions prior to the late 1970s when the virus was first identified. Since 1990, all donated blood has been tested for hepatitis C.

“It was not known in the '70s,” Dr. Ambrosino said.

The virus differs from hepatitis A, a largely food-borne illness, and hepatitis B, a more obvious illness, which is also transmitted through blood but was identified earlier and for which there is a vaccine.

The Massachusetts Biologic Institute was part of the state Department of Public Health until 1997, when it became aligned with UMass. Its main focus is public health — especially infectious diseases — and its major source of revenue is manufacturing tetanus-diphtheria vaccine and other medications. Monoclonal antibodies are the latest products, Dr. Ambrosino said.

- 90% of people with the 'CC' variation of IL28B who were new to treatment and received a telaprevir-based regimen achieved a viral cure, 78% of them were eligible to stop all treatment at 24 weeks -

- Nearly three-fold improvement in viral cure rates was observed among people with the 'CT' and 'TT' variations compared to the control group, regardless of prior treatment experience -

BERLIN--(March 31 2011 press release Vertex)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced new data from retrospective analyses that evaluated the relationship between variations at the IL28B gene and a patient's response to treatment with telaprevir in combination with pegylated-interferon and ribavirin from two of its pivotal Phase 3 studies (ADVANCE and REALIZE) for a group of people who were tested for IL28B genotype. These analyses showed that people in these studies had substantial improvements in sustained viral response (SVR, or viral cure) rates across all IL28B genotypes (CC, CT or TT) for those treated with telaprevir-based combination therapy compared to those treated with pegylated-interferon and ribavirin alone. Telaprevir is a medicine in development for the treatment of genotype 1 chronic hepatitis C. Safety and tolerability results were consistent across the Phase 3 studies of telaprevir. Data from these IL28B analyses were presented today at The International Liver Congress 2011, the 46th annual meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany.

A specific genetic region near the IL28B gene is referred to as an IL28B genotype. The three variations of IL28B genotypes have been associated with a person's response to hepatitis C treatment with pegylated-interferon and ribavirin. The CC variation is associated with better responses to these medicines.

"Doctors sometimes use IL28B genotype status to decide which patients should be treated with currently available medicines because people with the CT and TT variations of IL28B tend to have substantially lower viral cure rates compared to those with the CC variation," said Ira Jacobson, M.D., Chief of the Division of Gastroenterology and Hepatology at New York-Presbyterian Hospital/Weill Cornell Medical Center, and the Vincent Astor Distinguished Professor of Medicine at Weill Cornell Medical College and principal investigator for the ADVANCE study. "In this study, telaprevir was associated with a substantial improvement over currently available medicines, regardless of IL28B status, and the greatest improvement was observed in patients with the CT and TT variations."

In ADVANCE, patients were randomized 1:1:1 to receive telaprevir (eight weeks or 12 weeks) in combination with pegylated-interferon and ribavirin, followed by pegylated-interferon and ribavirin alone for a total of either 24 weeks or 48 weeks of treatment. Eligibility for the shorter treatment duration was based on having undetectable hepatitis C virus at weeks four and 12. Among patients in this study tested for their IL28B genotype, 90 percent (45/50) of CC patients who received a 12-week telaprevir-based combination regimen, achieved a viral cure and 78 percent (39/50) of them were eligible to stop all treatment at 24 weeks. These results were compared to 64 percent (35/55) of patients who achieved a viral cure with pegylated-interferon and ribavirin alone for 48 weeks.

"The 90 percent viral cure rate among people with the CC variation of IL28B in this study is significant, but the fact that nearly 80 percent of them were eligible for the shorter course of treatment is an equally important finding," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. "Vertex plans to conduct a study evaluating a short-duration, 12-week telaprevir-based regimen in people who have not been treated for hepatitis C who have the CC variation of IL28B."

Data from the ADVANCE study showed that patients with the CC variation of IL28B who were new to treatment and received a telaprevir-based combination regimen had the highest viral cure rates compared to those with the CT and TT variations. Data from both ADVANCE and REALIZE showed a nearly three-fold improvement in viral cure rates among patients with the CT and TT variations of IL28B who received telaprevir-based combination therapy compared to those who received pegylated-interferon and ribavirin. These differences were observed among patients who were new to treatment as well as those whose prior treatment for hepatitis C was unsuccessful.

Retrospective Analysis from ADVANCE

The Phase 3 ADVANCE study evaluated people who were new to treatment for hepatitis C. The retrospective analysis of IL28B status presented today includes people tested for IL28B genotype (454/1088; 42 percent). Of the patients in ADVANCE who were tested for their IL28B genotype, the distribution of the variations was consistent with previously published studies in people new to treatment.1 Data from the subanalysis of IL28B status in the control and telaprevir treatment arms (12 weeks) of the study are shown in the table.

Due to the de-identification procedure, only samples from Caucasian patients were included in this analysis.

The Phase 3 REALIZE study evaluated people whose prior treatment with pegylated-interferon and ribavirin was unsuccessful (prior relapsers, prior partial responders and prior null responders). Of the patients in REALIZE who were tested for their IL28B genotype (527/662; 80 percent), the distribution of patients with the CT variation was over-represented and the distribution of those with the CC variation was under-represented. This is consistent with expectations for a population that has not responded to a prior course of treatment.

Relapser: Defined as a person whose hepatitis C virus was undetectable at the completion of at least 42 weeks of a prior course of therapy but whose virus became detectable during the follow-up period.

Partial Responder: Defined as a person who achieved at least a 2 log10 reduction in HCV RNA at week 12, but whose hepatitis C virus never became undetectable by week 24 of a prior course of therapy.

Null Responder: Defined as a person who achieved a less than 2 log10 reduction in HCV RNA at week 12 of a prior course of therapy.

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Safety and Tolerability Information from Phase 3 Studies of Telaprevir

The safety and tolerability results of the telaprevir-based combination regimens were consistent across the Phase 3 studies. The most common adverse events were fatigue, pruritus, nausea, headache, rash, anemia, flu-like symptoms, insomnia and diarrhea with the majority being mild to moderate. Rash and anemia occurred more frequently in the telaprevir-based treatment arms compared to the control groups.

Rash was primarily characterized as eczema-like, manageable and resolved upon stopping telaprevir. More than 90 percent of rash was mild to moderate and was primarily managed with the use of topical corticosteroids and/or antihistamines. Anemia was primarily managed by reducing the dose of ribavirin.

To optimize each patient's opportunity to achieve viral cure in the Phase 3 studies, sequential discontinuation of the medicines was recommended as a strategy to manage certain adverse events. This strategy allowed patients to continue on pegylated-interferon and ribavirin after stopping telaprevir. Discontinuation of all medicines due to either rash or anemia during the telaprevir/placebo treatment phase was 1 percent to 3 percent in the telaprevir treatment arms.

About IL28B

IL28B is a gene related to the interferon system. A genetic region near the IL28B gene is referred to as an IL28B genotype. There are three variations of IL28B genotypes: CC, CT or TT. These variations have been associated with a person's response to treatment for hepatitis C with pegylated-interferon and ribavirin. Studies have shown that people with the CC variation respond better to treatment with pegylated-interferon and ribavirin than those with the CT or TT variations. The CC variation is more frequent in Caucasians compared to African Americans (39 percent versus 16 percent), which may partially explain the lower response to treatment observed among African Americans in most clinical trials of pegylated-interferon and ribavirin.1

About the Phase 3 ADVANCE and REALIZE Studies

ADVANCE was a pivotal Phase 3, randomized, double-blind, placebo-controlled, global study of 1,088 people who were new to hepatitis C treatment. The primary endpoint of ADVANCE was SVR (defined as the proportion of people who had undetectable hepatitis C virus 24 weeks after the end of all treatment; <25 IU/mL, undetectable by Roche COBAS Taqman HCV test). The secondary endpoint evaluated the safety of telaprevir when dosed in combination with pegylated-interferon and ribavirin.

REALIZE was a pivotal Phase 3, randomized, double-blind, placebo-controlled study conducted globally with the majority of clinical trial sites in Europe and North America. The study was designed to evaluate the efficacy, safety and tolerability of telaprevir-based combination regimens in people infected with genotype 1 chronic hepatitis C who did not achieve a viral cure after at least one course of prior treatment with interferon-based therapy.

Patients were randomized 2:2:1 to two telaprevir-based treatment arms (simultaneous start and lead-in) and a control arm of pegylated-interferon and ribavirin alone. The primary endpoint of the REALIZE study was SVR in each of the two telaprevir treatment arms compared to the control arm and for the three groups of people included in the study.

Status of Telaprevir Regulatory Applications

The regulatory applications for the approval of telaprevir have been granted Priority Review by the U.S. Food and Drug Administration (FDA) and Health Canada and accelerated assessment by the European Medicines Agency for the treatment of people with genotype 1 chronic hepatitis C. The FDA has scheduled its Antiviral Drugs Advisory Committee to discuss the New Drug Application for telaprevir on April 28, 2011. A target response date of May 23, 2011 is set under the Prescription Drug User Fee Act (PDUFA). The applications include data from three registration studies, ADVANCE, ILLUMINATE and REALIZE, which evaluated telaprevir in combination with pegylated-interferon and ribavirin in people with hepatitis C who were new to treatment as well as those who did not achieve a viral cure after treatment with currently available medicines. For complete information on the telaprevir clinical trials or a fact sheet on the trial designs visit: www.vrtx.com/press.cfm.

About the Telaprevir Development Program

Telaprevir is an investigational, oral inhibitor that acts directly on the HCV protease, an enzyme essential for viral replication. To date, more than 2,500 people with hepatitis C have received telaprevir-based therapy as part of Phase 2 studies and the Phase 3 ADVANCE, ILLUMINATE and REALIZE studies. Together, these studies enrolled people with genotype 1 chronic hepatitis C who had not been treated for their disease previously as well as people who had been treated before but did not achieve a viral cure.

Vertex is developing telaprevir in collaboration with Tibotec BVBA and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America. Through its affiliate, Janssen, Tibotec has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries.

About Hepatitis C

Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.2 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.2 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.2 Approximately 60 percent of people who undergo treatment with an initial 48-week regimen of pegylated-interferon and ribavirin, the currently approved medicines for genotype 1 hepatitis C, do not achieve SVR,3,4,5 or viral cure.6 If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.7,8

More than 170 million people worldwide are chronically infected with hepatitis C.6 In the United States, nearly 4 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.9 The majority of people with hepatitis C in the United States were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.10 Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 4,600 to 12,000 deaths annually.11,12 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.10

PEGASYS® and COPEGUS® are registered trademarks of Hoffmann-La Roche.

Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including statements regarding (i) Vertex's plan to conduct a study evaluating a short-duration, 12-week telaprevir-based regimen in people how have not been treated for hepatitis C who have the CC variation of IL28B, (ii) the date of the scheduled meeting of the FDA's Antivirial Advisory Committee and (iii) the FDA's target review date for the telaprevir NDA. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that Vertex could experience unforeseen delays in obtaining approval to market telaprevir; that there may be varying interpretations of the data from the telaprevir clinical trials; that future outcomes from clinical trials of telaprevir may not be favorable; that future scientific, clinical, competitive or other market factors may adversely affect the potential for telaprevir-based therapy and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex's website at www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

About Vertex

Vertex creates new possibilities in medicine. Our team aims to discover, develop and commercialize innovative therapies so people with serious diseases can lead better lives.

Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, epilepsy and other life-threatening diseases.

Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada.

BERLIN--(press release March 31 2011) Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced interim results from an ongoing Phase 2 study (ZENITH) designed to assess the safety and tolerability of 12-week response-guided treatment regimens with its polymerase inhibitor, VX-222, and its protease inhibitor, telaprevir, in combination with pegylated-interferon and ribavirin in people with genotype 1 chronic hepatitis C who were new to treatment. The study enrolled 106 people into one of four treatment groups. Among those who received VX-222 (400 mg) in combination with telaprevir, pegylated-interferon and ribavirin, interim data showed that 90 percent (27/30) of them had undetectable hepatitis C virus at week 12. Half (15/30) of those in the VX-222 (400 mg) treatment group were eligible to stop all treatment at week 12. People in this same treatment group who were not eligible to stop all treatment at 12 weeks were assigned to receive 24 total weeks of treatment: 12 weeks of the four-drug regimen followed by 12 weeks of pegylated-interferon and ribavirin alone. Preliminary safety results showed that the most frequently reported adverse events were mild gastrointestinal symptoms and mild fatigue. At the time of this analysis, there were no discontinuations due to gastrointestinal symptoms. Data from this study are being presented today at The International Liver Congress 2011, the 46th annual meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany.

"Telaprevir triple therapy demonstrated significant improvements in viral cure rates and an ability to halve treatment time to 24 weeks for many people in late-stage studies," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. "Reducing treatment time in half again to 12 weeks would be another important advance and the early data from this study provide new information about the potential to do this with a four-drug VX-222 regimen."

Using an intent-to-treat analysis, 57 percent (17/30) of people treated with VX-222 (400 mg) in combination with telaprevir, pegylated-interferon and ribavirin had undetectable hepatitis C virus by week two. Among people who were treated with VX-222 (100 mg) in combination with telaprevir, pegylated-interferon and ribavirin, 38 percent (11/29) had undetectable hepatitis C virus by week two. To determine if patients were eligible to stop all treatment at 12 weeks in ZENITH, they had to have undetectable hepatitis C virus at weeks two and eight. Using the eligibility criteria for a 12-week total treatment duration, half (15/30) of the patients in the high-dose VX-222 combination group and 38 percent (11/29) in the low-dose combination group were eligible to stop all treatment at 12 weeks. Ninety percent (27/30) of patients in the high-dose VX-222 group had undetectable hepatitis C virus by week 12 as did 83 percent (24/29) in the low-dose VX-222 group. No viral breakthrough was observed through week 12 among patients receiving the four-drug combinations.

"The early data from this study are encouraging because they showed patients had a very rapid decline in hepatitis C virus as early as the second week of treatment," said Adrian Di Bisceglie, M.D., Chief of Hepatology at Saint Louis University School of Medicine. "Hepatitis C virus was undetectable at week 12 of treatment in 90 percent of patients who received the higher dose of VX-222, and half of those in this treatment group were eligible to stop all treatment at that time."

ZENITH is an ongoing Phase 2 study that enrolled 106 people and began with four treatment arms evaluating two-drug and four-drug combination regimens. The primary endpoint is safety and tolerability and the secondary endpoint is on-treatment antiviral activity and the proportion of people in each treatment arm who achieve a sustained viral response (SVR, defined as undetectable hepatitis C virus 24 weeks after the end of treatment). The study is designed to evaluate various combinations of VX-222, telaprevir, pegylated-interferon and ribavirin for the treatment of genotype 1 chronic hepatitis C. In this study, VX-222, telaprevir and ribavirin are given twice daily. Arms A (n=18) and B (n=29) were designed to evaluate the all-oral, two-drug combination regimens of VX-222 (400 mg or 100 mg) and telaprevir (1,125 mg). Both of these study arms were discontinued due to a pre-defined stopping rule related to viral breakthrough. Arms C (n=29) and D (n=30) are ongoing and designed to evaluate the four-drug combination regimens of VX-222 (400 mg and 100 mg), telaprevir (1,125 mg), pegylated-interferon and ribavirin. An additional treatment arm has been added to the study to evaluate an all-oral, three-drug regimen of VX-222, telaprevir and ribavirin in people with genotype 1b chronic hepatitis C. This study arm is now open for enrollment. A sixth and final arm may be added to the trial per protocol based on data from the study.

HCV RNA was evaluated using the TaqMan assay version 2.0.

*As part of a response-guided regimen, people who have undetectable hepatitis C virus at weeks 2 and 8 are eligible to stop all treatment at week 12.

The 12-week safety and tolerability results are preliminary and include data on all patients enrolled in the study: those enrolled in the two-drug (n=47) and four-drug (n=59) treatment arms. The most frequent adverse events observed in this study were mild gastrointestinal symptoms (including diarrhea, nausea and vomiting) and mild fatigue. No patients discontinued due to gastrointestinal symptoms.

Preliminary safety data indicate that there were six discontinuations due to adverse events among the four treatment arms through week 12. There were two serious adverse events considered by the investigator to be potentially related to study medication: acute renal failure (Arm B), which resolved after study medications were discontinued and anemia (Arm C). There was one additional severe adverse event reported of pneumonia, septic shock and renal failure; this severe adverse event was considered by the investigator to be unrelated to study medication. The three additional discontinuations included rash (n=2) and a motor vehicle accident with facial fractures (n=1).

About Telaprevir and VX-222

Vertex has two oral medicines in development for the treatment of genotype 1 chronic hepatitis C: telaprevir and VX-222. Telaprevir is an investigational, oral inhibitor that acts directly on the HCV protease, an enzyme essential for viral replication. To date, more than 2,500 people with genotype 1 chronic hepatitis C have received telaprevir in Phase 2 and Phase 3 studies. Vertex has been granted Priority Review for its applications for the approval of telaprevir by the U.S. Food and Drug Administration (FDA) and Health Canada. The FDA has scheduled its Antiviral Drugs Advisory Committee to discuss the New Drug Application for telaprevir on April 28, 2011. A target response date of May 23, 2011 is set under the Prescription Drug User Fee Act (PDUFA).

Vertex is developing telaprevir in collaboration with Tibotec BVBA and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America. Through its affiliate, Janssen, Tibotec has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries.

VX-222 is an investigational, oral, non-nucleoside inhibitor of HCV NS5B polymerase. VX-222 is currently being evaluated in combination with telaprevir, pegylated-interferon and ribavirin in a Phase 2 study. Vertex has worldwide commercial rights for VX-222.

About Hepatitis C

Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.1 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.1 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.1 Approximately 60 percent of people who undergo treatment of an initial 48-week regimen of pegylated-interferon and ribavirin, the currently approved medicines for genotype 1 hepatitis C, do not achieve SVR,2,3,4 or viral cure.5 If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.6,7

More than 170 million people worldwide are chronically infected with hepatitis C.5 In the United States, nearly 4 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.8 The majority of people with hepatitis C in the United States were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.9 Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 4,600 to 12,000 deaths annually.10,11 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.9

PEGASYS® and COPEGUS® are registered trademarks of Hoffmann-La Roche.

Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including statements regarding (i) the potential importance of reducing treatment time to 12 weeks and early data from this study providing new information about the potential to do this with a four-drug VX-222 regimen; (ii) the early data being encouraging because the data showed patients had a very rapid decline in hepatitis C virus as early as the second week of treatment; (iii) the possibility that a sixth treatment arm may be added to the trial; (iv) the date of the scheduled meeting of the FDA's Antiviral Advisory Committee and (v) the FDA's target response date for the telaprevir NDA. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that Vertex could experience unforeseen delays in obtaining approval to market telaprevir; that the interim on-treatment data presented in this press release may not be predictive of the final outcomes from this clinical trial, outcomes from any future clinical trials of telaprevir/VX-222 may not be favorable; that future scientific, clinical, competitive or other market factors may adversely affect the potential for telaprevir/VX-222-based therapy and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex's website at http://www.vrtx.com/. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

About Vertex

Vertex creates new possibilities in medicine. Our team aims to discover, develop and commercialize innovative therapies so people with serious diseases can lead better lives.

Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, epilepsy and other life-threatening diseases.

Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada.

Significant tolerability advantages and a 50% reduction in dosing frequency support Locteron's attractiveness for use in new triple- and quad- combination regimens

OctoPlus N.V. ("OctoPlus" or the "Company") (Euronext: OCTO) announces that its licensee Biolex Therapeutics will present today final results from the Locteron® Phase IIb clinical study at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany. These data highlight important tolerability advantages of Locteron versus current HCV treatments. Jan Egberts, CEO of OctoPlus, comments: "These positive final results from the Phase IIb clinical study with Locteron further confirm the long term benefits of Locteron's controlled release mechanism. Our PolyActive technology has enabled the development of an interferon alpha with a significantly improved side effect profile, achieving both a 50% reduction in flu-like adverse events and substantially lower rates of depression compared to conventional interferon treatments. In combination with its reduced injection frequency, these benefits clearly position Locteron as the interferon of choice for future hepatitis C treatments." The following information was taken directly from Biolex' press release (see www.biolex.com).

Biolex announces that final 72-week results from its SELECT-2 Phase 2b trial of Locteron® for the treatment of hepatitis C are being presented today at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany. Data presented today show that Locteron achieved the SELECT-2 study objectives by demonstrating viral kinetics and response rates that were comparable with or exceeded the PEG-Intron® control while also achieving a statistically significant reduction in flu-like adverse events, reduced rates of depression, lower use of concomitant medications and a reduced rate of discontinuation due to adverse events. Locteron, the only controlled- release interferon alpha, is designed to offer key tolerability and dosing advantages over currently marketed interferons and serve as a core component of new combination therapies as the treatment of hepatitis C evolves to triple- and quad-drug regimens.

Locteron dosing convenience and efficacy

Locteron is administered once every other week and requires half as many injections as the currently marketed interferons, each of which are injected once per week. In SELECT-2, the sustained virologic response rate (SVR) for each of the three Locteron doses studied was comparable with or exceeded the response rate for the PEG-Intron control as outlined in the table below. Click on the link below for the press release including tables.

With the promise of two new drugs to fortify the current treatment protocol, doctors see promise of a better-tailored cocktail, similar to HIV treatments, to beat back this common and often debilitating infection

Some 3.2 million Americans have chronic hepatitis C, an infection that can linger in the body for years before producing symptoms. It can eventually lead to serious liver scarring and cancer. And most infections in the U.S. are the disease's particularly tough breed, known as genotype 1, which has a cure rate of less than 40 percent with the best current treatment.

Two new drugs for this type, however, are now racing toward approval by the U.S. Food and Drug Administration, which could come as soon as late May. Both compounds are protease inhibitors and are expected to hit the market at about the same time.

Hepatitis C is spread through contact with blood and occasionally other bodily fluids, and 65 to 70 percent of people infected with the disease are unaware that they have it, according to John Ward, director of the Division of Viral Hepatitis at the U.S. Centers for Disease Control and Prevention. In the U.S. about one in 30 baby boomers has hepatitis C, and one in four people with HIV has the infection, he noted at a 2010 talk. The disease is responsible for some $33.3 billion in medical costs each year.

"We've been waiting for these drugs for a long time," says Darryn Potosky, a hepatologist at the University of Maryland Medical Center, who often has to tell patients they face steep odds of beating the disease.

If the new drugs come to market, patients would take one or the other in addition to the current two-drug treatment regimen. "It seems hepatitis C therapy is moving in the direction of HIV therapy, with multiple drug cocktails," Potosky says. And with that come "hopes that we can tailor treatments to patients."

Two new studies of one of the drugs, boceprevir, will be published in the March 31 issue of the New England Journal of Medicine. Both phase III trials were funded by Schering-Plough (now part of Merck), which makes the drug. There have not yet been any studies comparing boceprevir and the other new protease inhibitor, telaprevir (made by Vertex), but given the drugs' similarity, experts say they both seem promising.

In the new boceprevir trials, adding the drug to the current standard treatment (of interferon and ribavirin) effectively doubled the percentage of patients who were able to suppress the virus—an effect called sustained viral response, which is a mark of being effectively "cured."

"Patients with hepatitis C genotype 1 infection can anticipate a significant therapeutic advance," says Donald Jensen, a professor of medicine at the University of Chicago Medical Center, who wrote an editorial on the new research for the same issue of NEJM. But because these new drugs will each need to be used in combination with the existing two-drug regimes, they "will be associated with more side effects and more complexity."

Long road to safety

Doctors have long hoped for a safe and effective drug to beat hepatitis C (HCV) genotype 1—which, among strains of the disease, is "the most common and the hardest to treat at the same time," Potosky says. Some 70 to 80 percent of people infected with hepatitis C in the U.S. have this type.

With excitement building for these new drugs to arrive in the market, those who have been working on the problem have not forgotten that getting to this point "has been painstakingly slow," says Stuart Gordon of Henry Ford Hospital in Detroit, who coauthored one of the new studies.

Just finding the right compounds was challenging, he notes. An early protease-inhibitor contender, made by Boehringer Ingelheim, was found to be too toxic, and "many of the HCV polymerase inhibitors had to stop their development because of unacceptable side effects," Gordon notes.

And because the new treatment regime must be shown to be better than the current standard of care, which is a 48-week course, "the sheer time involved in conducting these large trials" made for slow going. But a payoff might be near.

One new trial, of 1,097 patients with hepatitis C genotype 1 who had never been treated, found that after 24 or 44 weeks of adding boceprevir to their drug regimen some two-thirds of non-black patients showed they were effectively suppressing the virus. The drug combo was not as effective for black patients, who are less likely to have a gene alteration that is linked to responsiveness to one of the drugs. But adding boceprevir still boosted response rates in these patients from 23 percent to more than half in the 44-week treatment group.

In the other trial, 403 patients with the disease who had not responded to traditional treatment—either showing no improvement or relapsing—were studied. Adding boceprevir to the standard treatment for 32 or 44 weeks resulted in sustained viral response rates in 59 and 66 percent of patients, respectively, compared with 38 percent in the control group.

The studies were both somewhat unusual in that they started patients out with a month-long lead-in period in which patients received the two drugs already available—before boceprevir was introduced to some groups. This "allowed some prediction capability of both subsequent response as well as risk of developing resistant variants," Jensen explains.

Early studies showed that although a protease inhibitor given on its own was very effective initially, it often led to resistant strains of the virus in a matter of days, Gordon says. Even with interferon and ribavirin, resistance "remains a concern," he says. To keep it to a minimum, "clinicians must follow such patients very closely during therapy because if the viral level starts to rise after initially declining, then the protease inhibitor must be stopped to prevent the development of even more resistant strains."

Potosky notes that the extent of resistance will only become clear with time—and as more people take the new drugs. And just as they monitor HIV patients for telltale resistance patterns, doctors should be able to detect early signs of resistance in people being treated for hepatitis C as well.

Adding boceprevir also increased the amount of side effects patients experienced. More than 40 percent of subjects taking this third drug required treatment for anemia in one of the studies, and in the other, severe anemia led doctors to decrease dosage in some 20 percent of subjects. Even though some of these cases were serious, few patients dropped out of treatment.

With boceprevir and telaprevir likely in the home stretch to reach potentially millions of hepatitis C patients in the U.S., doctors and researchers are now turning their focus to the many challenges that remain.

Aside from keeping resistance low and dialing down side effects, the next steps are to try to simplify the treatment regimen. "Everyone wants to get rid of interferon and ribavirin because both have toxicity that make them often difficult to tolerate," Gordon notes. Interferon also currently is usually administered via injection, so moving to an all-oral, once-a-day dosing would make treatment better and more consistent.

Gordon also looks forward to finding ways to help special populations of patients, including those who have HIV, end-stage liver disease or renal disease, as well as children, "who are currently not eligible for our current therapies."

In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment.

Methods

To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks.

Results

A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log10 IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls.

A total of 640 patients were evaluated for enrollment in the study; 403 were enrolled and underwent randomization and treatment (Figure S1 in the Supplementary Appendix). The baseline demographic characteristics were balanced among the three treatment groups (Table 1Table 1Baseline Characteristics of the Patients, According to Treatment Group.), with the exception of high viral load (group 2 vs. group 1, P=0.04). The mean age was 52.7 years, 12% of patients were black, and the mean body weight was 84.9 kg. Approximately 88% of patients had a high viral load (an HCV RNA level >800,000 IU per milliliter) at baseline. The prevalence of infection with HCV genotypes 1a and 1b was similar (47% and 44%, respectively). A total of 19% of patients had a Metavir fibrosis score of 3 or 4. The majority of patients (64%) had had a relapse after previous HCV therapy.

Efficacy

In the primary-analysis population, rates of sustained virologic response were significantly higher among patients receiving boceprevir than among those treated with peginterferon-ribavirin alone (Figure 2Figure 2Patients with a Sustained Virologic Response, According to Treatment Group and Analysis.), with overall rates of sustained virologic response of 21%, 59%, and 66% in groups 1, 2, and 3, respectively (P<0.001). This increase seen with boceprevir was due largely to end-of-treatment rates of response (i.e., an undetectable HCV RNA level) that were greater in group 2 (70%) and group 3 (77%) than in group 1 (31%), as well as a decreased rate of relapse in group 2 (in 17 of 111 patients [15%]) and group 3 (in 14 of 121 patients [12%]) as compared with group 1 (in 8 of 25 patients [32%]). Viral breakthrough and incomplete virologic response were infrequent during the treatment period (with either occurring in 1 of 80 patients [1%] in group 1, in 9 of 162 patients [6%] in group 2, and in 7 of 161 patients [4%] in group 3).

The rates of sustained virologic response among patients with prior relapse were 29% in group 1, versus 69% and 75% in group 2 and group 3, respectively; among patients with prior nonresponse, the corresponding rates were 7% versus 40% and 52%. A total of 102 patients (15%, 28%, and 27% in groups 1, 2, and 3, respectively) had a poor response to interferon, defined as a decrease in the HCV RNA level of less than 1 log10 IU per milliliter after the 4-week lead-in period (Figure 2). In this subgroup, a sustained virologic response was achieved in none of the patients in group 1 and in 33% and 34% in groups 2 and 3, respectively. Among patients who had a good response to interferon (a decrease in HCV RNA level of 1 log10 IU per milliliter or more at treatment week 4), the rates of sustained virologic response were 25%, 73%, and 79% in group 1, group 2, and group 3, respectively.

An assessment for amino acid variants associated with reduced susceptibility to boceprevir was performed for 114 patients in group 2 or group 3 in whom a sustained virologic response did not occur. Postbaseline data were available for 98 of the 114 patients (86%), with variants detected in 43 of these 98 patients (44%). The rate of amino acid variants associated with reduced susceptibility to boceprevir was higher among patients with a poor response to interferon (13 of 46 [28%] in group 2 and 15 of 44 [34%] in group 3) than among patients with a good response to interferon (10 of 110 [9%] in group 2 and 7 of 112 [6%] in group 3).

In group 2, the duration of total therapy was based on a prespecified decision at treatment week 8, at which time patients with an undetectable HCV RNA level were eligible for a shorter period of therapy. The proportion of patients with an undetectable HCV RNA level at week 8 in the boceprevir groups (74 of 162 patients [46%] in group 2 and 84 of 161 patients [52%] in group 3) was approximately six times the proportion in group 1 (7 of 80 [9%]). Early response (i.e., an undetectable HCV RNA level at week 8) was associated with high rate of sustained virologic response in all three groups (7 of 7 patients [100%] in group 1; 64 of 74 patients [86%] in group 2; and 74 of 84 patients [88%] in group 3).

An evaluation of treatment effect according to subgroups of baseline characteristics showed that the numerical odds of a sustained virologic response was greater, across all subgroups, with either response-guided triple therapy (group 2) or 44-week triple therapy (group 3) than with the standard of care (group 1) (Figure 3Figure 3Odds Ratios for a Sustained Virologic Response in Group 2 versus Group 1 and Group 3 versus Group 1, According to Subgroup.).

Although there was a sustained virologic response in 12 more patients in group 3 than in group 2, the rates in each group did not differ significantly (odds ratio of a sustained virologic response in group 3 vs. group 2, 1.4; 95% confidence interval, 0.9 to 2.2). A similarly small difference was seen between these two groups during the period in which the therapy was identical (week 0 through treatment week 36), with 9 to 14 more patients having an undetectable HCV RNA level during treatment weeks 8 to 36 in group 3 than in group 2 (Figure S2 in the Supplementary Appendix). In post hoc exploratory analyses, we observed that this difference appeared to be driven by patients with cirrhosis at baseline: the percentage of patients with cirrhosis who had an undetectable HCV RNA level at week 8 was 18% (3 of 17 patients) in group 2, versus 73% (16 of 22 patients) in group 3, despite identical treatment through this time point (Figure S2 in the Supplementary Appendix). This suggests an underlying difference in responsiveness that is not fully accounted for by treatment-group randomization. In contrast, among patients without cirrhosis at baseline, the percentage with an undetectable HCV RNA level at week 8 was 50% (66 of 132 patients) in group 2 and 49% (63 of 128) in group 3. The odds of a sustained virologic response were similar between group 3 and group 2 for most baseline factors except for body weight under 75 kg, elevated alanine aminotransferase level, and cirrhosis, for which there was a greater odds of a sustained virologic response in group 3 (Figure S3 in the Supplementary Appendix). In contrast, the odds of a sustained virologic response were not different for those with advanced fibrosis (a Metavir fibrosis score of 3 or 4), which is often preferentially used owing to the variability of biopsy readings.

Multivariable stepwise logistic-regression analysis served to identify five baseline factors that were significantly associated with achievement of a sustained virologic response: assignment to either boceprevir group rather than the control group (odds ratios for group 2 and group 3 vs. group 1, 7.3 and 10.7, respectively; P<0.001 for both comparisons), previous relapse (odds ratio vs. previous nonresponse, 3.1; P<0.001), low viral load at baseline (odds ratio vs. high load, 2.5; P=0.02), and absence of cirrhosis (odds ratio vs. presence, 2.1; P=0.04) (Table S1 in the Supplementary Appendix). When the decline in viral load (i.e., decrease from baseline in the HCV RNA level of ≥1.0 log10 IU per milliliter vs. <1.0 log10 IU per milliliter) at week 4 (was added to the model, the week 4 response was a stronger predictor of sustained virologic response than historical response (odds ratio, 5.2; P<0.001).

Safety

The study included a stopping rule whereby patients in whom an undetectable HCV RNA level was not achieved by treatment week 12 discontinued all therapy. The low rate of an undetectable HCV RNA level by treatment week 12 in group 1 resulted in 61% of patients discontinuing treatment for this reason, as compared with 22% and 18% of patients in group 2 and group 3, respectively (Figure S1 in the Supplementary Appendix). Thus, the median duration of treatment was 2.4 to 3.2 times longer in the boceprevir groups than in the control group (Table 2Table 2Adverse Events, According to Treatment Group.).

In the boceprevir groups as compared with the control group, a greater proportion of patients reported serious adverse events and there were more discontinuations and dose modifications owing to adverse events. There was a higher incidence of anemia in the groups receiving boceprevir (43 to 46%) than in the control group (20%). Consistent with the increased incidence of anemia, the proportion of patients with hemoglobin levels of 6.5 to less than 9.5 g per deciliter was higher in groups 2 and 3 than in group 1; however, discontinuation owing to anemia was infrequent (occurring in 0% of patients group 1 and group 2 and in 3% [5 of 161 patients] in group 3). Erythropoietin was administered to 21%, 41%, and 46% of patients in groups 1, 2, and 3, respectively. Of the 403 patients, 17 received a transfusion for the management of anemia; 16 of these patients also received erythropoietin. Adverse events, dose modifications, and study-drug discontinuation in the 49 patients with cirrhosis are summarized in Table S3 in the Supplementary Appendix.

The most common adverse events observed in all treatment groups were flulike symptoms that are typically reported in association with peginterferon-ribavirin therapy (Table S5 in the Supplementary Appendix). Dysgeusia, rash, and dry skin were reported more commonly in the boceprevir groups than in the control group.

Discussion

Our data show that the addition of boceprevir to peginterferon-ribavirin therapy leads to high rates of sustained virologic response among patients in whom prior treatment had failed. Furthermore, patients who had previously had a relapse after receiving the standard of care had rates of sustained virologic response of up to 75%, with rates of 40 to 52% in the subgroup of patients with a previous nonresponse. Patients with undetectable HCV RNA levels at treatment week 8 were shown to have a rate of sustained virologic response that was similar whether boceprevir was taken for 32 weeks or 44 weeks; thus, an early response identified patients who could benefit from shorter treatment. There were no identified groups of patients with a previous treatment failure for whom the standard of care was more efficacious than was triple therapy. We observed high rates of a sustained virologic response among black patients and patients with advanced liver disease, who usually have a poor response,17,18 representing a clinically significant improvement over the standard of care.19

Rates of anemia were higher among patients receiving boceprevir-containing regimens than among those receiving control therapy, and many patients required erythropoietin treatment. Discontinuation for anemia was infrequent (affecting 3% of patients in group 3 only). Consistent with the increased incidence of anemia, a higher proportion of boceprevir recipients, as compared with controls, had a neutrophil count of 500 to less than 750 per cubic millimeter or underwent a red-cell transfusion.

This study included a 4-week lead-in period during which peginterferon-ribavirin was administered, which allowed for the assessment of the patient's interferon responsiveness immediately before the addition of boceprevir. We have previously shown that a decline in viral load of less than 1 log10 IU per milliliter after 4 weeks of peginterferon-ribavirin therapy is significantly correlated to a decline of less than 2 log10 IU per milliliter after 12 weeks of treatment.20 We identified 102 patients with a poor response to interferon, defined as a decrease in the HCV RNA level of less than 1 log10 IU per milliliter at week 4. This is an important recognition of the changes that can evolve over time in patients who had previously been treated and are awaiting retreatment. Possible explanations for such changes include an increase in body weight, development of glucose intolerance, an increase in hepatic steatosis, and progression of fibrosis, all of which could have resulted in diminished responsiveness to peginterferon-ribavirin. Notably, a sustained virologic response was achieved, after boceprevir was added to the standard of care, in 33 to 34% of the patients with a poor response to interferon, as compared with 0% in the patients retreated with peginterferon-ribavirin alone.

In summary, the results of our phase 3 trial show that boceprevir, when added to peginterferon alfa-2b and ribavirin, leads to high rates of sustained virologic response in difficult-to-treat patients.

The opinions expressed in this report represent the consensus of the authors and do not necessarily reflect the formal position of Merck or other institutions listed as authors' affiliations.

Sponsored by Schering-Plough (now part of Merck).

Methods

Study Oversight

The study protocol is available with the full text of this article at NEJM.org. The trial (HCV RESPOND-2 [Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2]) was funded by Schering-Plough (now part of Merck) and was designed, managed, and analyzed by Merck in conjunction with the external academic investigators and members of the external data and safety monitoring board. The academic authors had agreements with the sponsor concerning the confidentiality of the data. The academic authors collected the data, which was then analyzed by the sponsor. The sponsor held the data and made them available to the academic authors. The first draft of the manuscript was written by one academic author and three industry authors. All authors were involved in the collection, analysis, or interpretation of the data; revision of the manuscript; and the decision to submit the manuscript for publication. All authors vouch for the completeness and accuracy of the data and analyses as well as the fidelity of the study to the protocol.

Study Patients

From August through November 2008, we screened 640 patients with HCV genotype 1 infection at 80 sites in North America and Europe. Eligibility criteria included demonstrated responsiveness to interferon (minimum duration of therapy, 12 weeks). We defined patients as having either nonresponse (i.e., a decrease in the HCV RNA level of at least 2 log10 IU per milliliter by week 12 but with a detectable HCV RNA level during the therapy period) or relapse (i.e., an undetectable HCV RNA level at the end of treatment, without subsequent attainment of a sustained virologic response [i.e., with a detectable HCV RNA level during the follow-up period]).

Exclusion criteria included hepatitis B or infection with the human immunodeficiency virus, any other cause of clinically significant liver disease, decompensated liver disease, uncontrolled diabetes mellitus, a severe psychiatric disorder, and active substance abuse. Liver-biopsy specimens were assessed for Metavir fibrosis scores and steatosis scores by a single academic author who is a pathologist and was unaware of the assignment of boceprevir or placebo. Possible Metavir fibrosis scores are as follows: a score of 0 indicates no fibrosis, 1 indicates portal fibrosis without septa, 2 indicates portal fibrosis with few septa, 3 indicates numerous septa without cirrhosis, and 4 indicates cirrhosis.

Study Design

The primary objective was to compare two treatment regimens containing boceprevir in combination with open-label peginterferon alfa-2b and ribavirin (PegIntron and Rebetol, respectively; Merck) to treatment with peginterferon-ribavirin plus placebo in previously treated adults with chronic HCV genotype 1 infection. Our study was conducted in accordance with the principles of Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies. All patients provided written informed consent before randomization.

Patients were randomly assigned, in a 1:2:2 ratio with the use of an interactive voice-response system, to one of three treatment groups, with stratification according to previous response to therapy (nonresponse or relapse) and HCV subgenotype (1a or 1b) as determined by means of sequencing of the HCV 5' noncoding region (Trugene).13 Patients with HCV genotype 1 infection whose HCV subtype could not be classified were randomly assigned to one of the treatment groups. The HCV genotype 1 subtype was also determined by means of sequencing of the nonstructural 5B (NS5B) region (Virco).

The study design is illustrated in Figure 1Figure 1Study Design.. For purposes of the study doses, peginterferon alfa-2b was administered subcutaneously at a dose of 1.5 μg per kilogram of body weight once weekly, and ribavirin was administered at a divided daily dose of 600 to 1400 mg per day on the basis of body weight. Treatment with boceprevir consisted of oral administration at a dose of 800 mg three times daily (to be taken with food and with an interval of 7 to 9 hours between doses) in four capsules of 200 mg each. Placebo was matched to boceprevir. The study was double-blinded regarding the administration of boceprevir.

During the 4-week lead-in period, all patients received peginterferon plus ribavirin. Subsequent treatment varied according to group. Group 1 (the control group) received peginterferon-ribavirin plus boceprevir-matched placebo for 44 weeks. Group 2 received a response-guided therapy regimen consisting of boceprevir plus peginterferon-ribavirin, for 32 weeks; according to the week 12 stopping rule, patients with an undetectable HCV RNA level at weeks 8 and 12 completed therapy at week 36, whereas those with a detectable HCV RNA level at week 8 (but an undetectable level at week 12) received peginterferon-ribavirin plus placebo for an additional 12 weeks. Group 3 received boceprevir and peginterferon-ribavirin for 44 weeks.

The stopping rule applied in all groups was that failure to achieve an undetectable HCV RNA level at week 12 resulted in discontinuation of all treatment and advancement to follow-up.

Plasma HCV RNA levels were measured with the use of the TaqMan 2.0 assay (Roche Diagnostics), which has lower limits of quantification and detection of 25 and 9.3 IU per milliliter, respectively; the lower limit of detection was used for decision making at various points throughout the study.13 Measurement was performed at the screening visit, at baseline, every 2 weeks through week 12, and then at weeks 16, 20, 24, 30, 36, 42, and 48, as well as at weeks 4, 12, and 24 of the follow-up period.

Safety

Adverse events were graded by investigators according to a modified World Health Organization grading system. Non-life-threatening adverse events were managed by means of dose reduction. The recommended guidelines for a two-step dose reduction of peginterferon and for a three-step dose reduction of ribavirin were similar to those previously described (as is summarized in the Supplementary Appendix, available at NEJM.org).7,14-16

Viral breakthrough was defined as achievement of an undetectable HCV RNA level and subsequent occurrence of an HCV RNA level greater than 1000 IU per milliliter. Incomplete virologic response and rebound was defined as an increase of 1 log10 IU per milliliter in the HCV RNA level from the nadir, with an HCV RNA level greater than 1000 IU per milliliter (if both samples being compared were collected the same number of days after the last peginterferon injection). In cases in which the timing between the peginterferon injection and the HCV RNA sample collection was different for the two samples, an increase of 2 log10 IU per milliliter was required to meet this criterion. If a patient had virologic breakthrough or an incomplete virologic response and rebound while receiving therapy, boceprevir treatment could be discontinued, but peginterferon-ribavirin could be continued for up to 48 weeks with appropriate clinical follow-up.

Statistical Analysis

Analyses regarding the primary objective included data from all patients who received at least one dose of any study medication. The key secondary objective was to compare the two boceprevir regimens with the peginterferon-ribavirin regimen in patients who completed the lead-in period and received at least one dose of placebo or boceprevir. Specifically, comparisons for the primary and key secondary objectives were made between group 3 and group 1 and between group 2 and group 1.

The primary efficacy end point was a sustained virologic response, defined as an undetectable plasma HCV RNA level at week 24 of the follow-up period. Secondary and other efficacy analyses were performed to calculate the proportion of patients with an early response (i.e., an undetectable HCV RNA level at week 8) in whom a sustained virologic response was achieved, as well as the proportion of patients with a relapse.

The primary statistical comparison was carried out with the use of a two-sided Cochran-Mantel-Haenszel chi-square test with adjustment for the baseline stratification factors. The study had a statistical power of 90% to detect an absolute improvement in the rate of sustained virologic response by 21 percentage points over the rate in group 1 (assuming response rates of 22% in the control group and 43% in the boceprevir groups) with the use of a two-sided chi-square test and an alpha value of 0.05.

To control for type I error in the primary analysis, a step-down approach was used. Group 3 was first compared against group 1. If the P value for the comparison was less than 0.05, the next comparison - of group 2 and group 1 - was carried out. A similar step-down approach was prespecified to control for the type I error regarding the key secondary objective. To account for multiplicity between the primary and key secondary analyses, the key secondary analyses were conducted only if the significance of the primary comparisons was established. P values calculated for sustained virologic response are provided for only the two prespecified primary and key secondary comparisons.

Summary statistics are reported for each of the three treatment regimens for subgroups of patients defined according to prespecified baseline characteristics. Multivariable logistic-regression analyses involving treatment regimen and prespecified baseline characteristics were performed to evaluate sustained virologic responses. A stepwise procedure was used to identify independent predictors of sustained virologic response (with P=0.05 as the threshold level for variables to be entered into the model and retained in the final model). In addition, we fit a stepwise logistic-regression model of the response (decrease from baseline in the HCV RNA level of ≥1.0 log10 IU per milliliter vs. <1.0 log10 IU per milliliter) at treatment week 4 and baseline characteristics.

Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies.

Methods

We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately.

Results

A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively.

Conclusions

The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.)

The opinions expressed in this report represent the consensus of the coauthors and do not necessarily reflect the formal position of Merck or the other institutions listed as authors' affiliations.

Supported by Schering-Plough (now Merck).

Chronic infection with the hepatitis C virus (HCV) affects more than 170 million people worldwide.1,2 Rates of sustained virologic response associated with peginterferon-ribavirin therapy remain below 50% and are often less than 30% among patients who have HCV genotype 1 infection and certain baseline characteristics, such as advanced fibrosis, diabetes, coinfection with the human immunodeficiency virus (HIV), or African heritage.3-9 Recent efforts to improve the rate of sustained virologic response have focused on oral direct-acting antiviral agents.10-13

Boceprevir is a linear peptidomimetic ketoamide serine protease inhibitor that binds reversibly to the HCV nonstructural 3 (NS3) active site.14 Like other protease inhibitors, boceprevir must be given with peginterferon-ribavirin to minimize the emergence of viral resistance. 15,16 In the SPRINT-2 (Serine Protease Inhibitor Therapy 2) trial, we examined whether the addition of boceprevir to standard therapy could improve the rates of sustained virologic response in previously untreated patients infected with HCV genotype 1.

Results

Study Patients

A total of 1246 and 226 patients were screened for the nonblack cohort and the black cohort, respectively, of whom 940 nonblack patients and 159 black patients were randomly assigned to a treatment group from August 2008 through January 2009 (Figure S1 in the Supplementary Appendix). Two patients in the nonblack cohort did not receive any study drug and were not included in the analyses. All the other randomly assigned patients received at least 1 dose of study medication. Baseline characteristics are shown in Table 1Table 1Selected Baseline Characteristics of Patients Who Received at Least One Dose of Study Medication, According to Cohort and Treatment Group.

A total of 49 patients discontinued the peginterferon-ribavirin therapy during the lead-in period and did not receive boceprevir or placebo. Discontinuation for reasons of futility at week 24 occurred in 84 of 311 patients (27%), 24 of 316 patients (8%), and 28 of 311 patients (9%) in the nonblack cohort and in 24 of 52 patients (46%), 9 of 52 patients (17%), and 8 of 55 patients (15%) in the black cohort in groups 1, 2, and 3, respectively.

Efficacy

Response rates were significantly higher among patients receiving a boceprevir-containing regimen than among controls (Table 2Table 2Rates of Virologic Responses among Patients Who Received at Least One Dose of Any Study Medication, According to Cohort and Treatment Group.). Among nonblacks, the rate of a sustained virologic response was 40% with the standard of care and was significantly higher (P<0.001) in both boceprevir groups - 67% in group 2 and 68% in group 3 - for relative increases of 68% and 70%, respectively, over control rates. Among blacks, the rate of a sustained virologic response was 23% in group 1, 42% in group 2 (P=0.04, vs. group 1), and 53% in group 3 (P=0.004, vs. group 1). In a modified intention-to-treat analysis that included all nonblacks receiving at least one dose of boceprevir or placebo, the respective rates of sustained virologic response in groups 1, 2, and 3 were 42%, 70% (P<0.001, vs. group 1), and 71% (P<0.001, vs. group 1), the corresponding rates among blacks were 26%, 47% (P=0.04, vs. group 1), and 53% (P=0.01, vs. group 1). In the nonblack cohort, viral breakthrough occurred in 1 to 2% of patients in each treatment group, whereas rates of relapse were lower in the two boceprevir groups than in the standard-therapy group. The numbers of events in the smaller black cohort were too few to permit comparison between treatment groups.

The 4-week lead-in period of peginterferon-ribavirin treatment allowed for the assessment of interferon responsiveness and its relationship to sustained virologic response. At week 4, 23% of nonblacks and 38% of blacks had a decrease of less than 1 log10 IU per milliliter in the HCV RNA level from baseline, which was associated with lower rates of sustained virologic response (Table 2) and higher rates of boceprevir-resistance-associated variants (genotypic mutations of the protease conferring reduced sensitivity to boceprevir) (Table 3Table 3Common Clinical Adverse Events, Resistance-Associated HCV Variants, and Hematologic Abnormalities, According to Treatment Group.) than was a decrease of 1 log10 IU per milliliter or more in the HCV RNA level, regardless of the treatment group. However, whether the decrease in the HCV RNA level at week 4 was more or less than 1 log10 IU per milliliter, rates of sustained virologic response were consistently higher in the boceprevir groups than in the control group.

The percentages of patients with undetectable HCV RNA levels at week 8 who had a sustained virologic response were high, irrespective of the treatment regimen, but this response at week 8 occurred approximately three times as often in the boceprevir groups as in the control group. At this time point, the patients had received boceprevir or placebo for 4 weeks and peginterferon-ribavirin for 8 weeks.

The rates of sustained virologic response among nonblacks were similar in group 2 (67%) and in group 3 (68%), whereas among blacks they were 42% and 53%, respectively. Among nonblack boceprevir recipients whose HCV RNA levels became undetectable by week 8 (60%) and those with undetectable HCV RNA levels through week 24 (47%), the rate of sustained virologic response was 97% in group 2 (which had received 24 weeks of boceprevir and a total of 28 weeks of therapy) and 96% in group 3 (which had received 44 weeks of boceprevir and a total of 48 weeks of therapy) (Table 2).

In group 2, a total of 22% of the patients with a detectable HCV RNA level between week 8 and week 24 received therapy for more than 28 weeks. Among patients in whom HCV RNA levels were still detectable at week 8, rates of sustained virologic response were 74% in group 2 (after receiving 24 weeks of boceprevir) as well as in group 3 (after receiving 44 weeks of boceprevir).

Predictors of sustained virologic response were identical in models for each cohort. Rates of sustained virologic response in patients with advanced fibrosis were lower than in those with mild fibrosis, although the numbers of patients with a Metavir fibrosis score of 3 or 4 (indicating bridging fibrosis or cirrhosis) were small, particularly in the black cohort (Table 4Table 4Odds Ratios for a Sustained Virologic Response, According to Predictor Variables.). In an expanded model that included virologic responses during the treatment period, a decrease in the HCV RNA level by 1 log10 IU per milliliter or more at the end of the 4-week lead-in period was strongly predictive of a sustained virologic response (odds ratio vs. a decrease of <1 log10 IU per milliliter, 9.0; 95% confidence interval, 6.3 to 12.8; P<0.001). In general, subgroup analyses across a range of baseline factors favored group 2 and group 3 over group 1, with no consistent differences between groups 2 and 3 (Figure S2 in the Supplementary Appendix). For groups 1, 2, and 3 in the nonblack cohort, rates of sustained virologic response were 33%, 64%, and 59%, respectively, among patients with a hemoglobin level of 10 g per deciliter or higher during the treatment period, as compared with 60%, 72%, and 79%, respectively, among patients with a nadir hemoglobin level of less than 10 g per deciliter during the treatment period.

Safety

Adverse events occurred in more than 98% of the study patients, with serious adverse events in 9%, 11%, and 12% of patients in groups 1, 2, and 3, respectively (Table S2 in the Supplementary Appendix). There were six deaths during the study: four patients in the control group died, as did two patients in the boceprevir groups. Two suicides (one in group 1 and one in group 2) were judged to have possibly been related to peginterferon. No other deaths were considered to be drug-related.

Fatigue, headache, and nausea were the most common clinical adverse events in all treatment groups (Table 3). Dysgeusia occurred more than twice as often in boceprevir recipients than in controls. Anemia was reported as an adverse event in 29% of controls and 49% of boceprevir recipients. Anemia was classified as grade 1 in 36% of controls, grade 2 in 17%, grade 3 in 2%, and grade 4 in 0%; the respective percentages among boceprevir recipients were 43%, 31%, 3%, and 1%. Four patients in group 1 discontinued the study owing to anemia, as compared with six patients in group 2 and seven patients in group 3. Overall, 13% of controls and 21% of boceprevir recipients required dose reductions because of anemia. Erythropoietin was administered in 24% of controls and 43% of boceprevir recipients. A total of 85% and 86% of patients in group 2 and group 3, respectively, had neutropenia of grade 1 to 4, as compared with 77% of those in the control group; 28% and 33% of patients in groups 1 and 2, respectively, had grade 1 to 4 thrombocytopenia, as compared with 13% of controls.

Discussion

SPRINT-2 compared two regimens of boceprevir added to peginterferon alfa-2b-ribavirin therapy (the standard of care) and the standard of care alone. Two distinct cohorts were enrolled on the basis of self-identified race (nonblack patients and black patients) to allow for an independent estimate of rates of response among black patients, a group historically underrepresented in HCV-treatment trials.

As compared with peginterferon alfa-2b-ribavirin therapy alone, the addition of boceprevir significantly increased the rate of a sustained virologic response among previously untreated black and nonblack patients infected with HCV genotype 1, including those with a decrease of less than 1 log10 IU per milliliter in the HCV RNA level at week 4. Among nonblack patients, the combination therapy with boceprevir was associated with a relative increase of approximately 70% in the rates of sustained virologic response over standard therapy. Although lower among black patients than among nonblack patients, the rates of sustained virologic response with the boceprevir regimens were nearly double those with the standard of care. Patients with an undetectable HCV RNA level at week 8 had a higher rate of sustained virologic response than patients with a detectable level at week 8, irrespective of treatment regimen. Given the relatively small numbers of patients with cirrhosis in the trial, further study is warranted to define optimal therapy in this population.

Our study evaluated a response-guided treatment strategy with individualized treatment duration on the basis of the HCV RNA level between weeks 8 and 24. Patients in whom the HCV RNA level became undetectable by week 8 and remained so up to week 24 were given boceprevir plus peginterferon-ribavirin for 24 weeks. The rates of sustained virologic response among both black and nonblack patients were significantly higher with response-guided therapy than with standard treatment. Regardless of the virologic response at week 4 or week 8, response-guided therapy that included 24 weeks of boceprevir administration resulted in overall rates of sustained virologic response that were similar to those after 44 weeks of triple therapy. Patients who had undetectable HCV RNA levels by week 8 had very high rates of sustained virologic response as compared with patients who had detectable levels between weeks 8 and 24. There were too few black patients in whom the HCV RNA level was detectable between weeks 8 and 24 to conclusively define the optimal treatment for this population.

This trial featured the use of peginterferon-ribavirin for 4 weeks (the lead-in period) before boceprevir was added. Theoretically, a lead-in phase would serve to lower HCV RNA levels before exposure to a protease inhibitor, thereby reducing the risk of viral breakthrough or resistance to the direct-acting antiviral agent, as noted in a phase 2 study in which boceprevir with lead-in therapy was compared with boceprevir without lead-in therapy.10 However, lead-in therapy has other benefits, such as allowing for assessment of the relationship between interferon responsiveness and subsequent sustained virologic response in patients receiving boceprevir. Patients with a poor response to interferon, defined as a reduction in the HCV RNA level of less than 1 log10 IU per milliliter after 4 weeks of peginterferon-ribavirin therapy, had sufficiently high rates of sustained virologic response, as compared with the control group, to dispel concern that the addition of a protease inhibitor to the treatment regimen would be equivalent to functional monotherapy. However, these patients were less likely than patients with a robust response to interferon to have a sustained virologic response after boceprevir was added.17-19 Thus, patients who have a poor response to interferon may need to be monitored closely to determine who may benefit from better therapies, once they are available. Conversely, in patients with undetectable HCV RNA levels after the lead-in period, boceprevir administration may not result in a higher rate of sustained virologic response than that achieved with the use of peginterferon and ribavirin alone. The lead-in period can further serve to test both compliance and tolerability before exposure to a class of drugs to which resistance can develop.15,16

The regimens that included boceprevir were associated with increased rates of anemia, and nearly twice as many boceprevir recipients as controls had a hemoglobin level of less than 9.5 g per deciliter or received erythropoietin (43% vs. 24%). Among patients receiving erythropoietin, the average duration of use was shortest in group 2. Neither the incidence of serious adverse events nor the frequency of discontinuation owing to an adverse event differed significantly between patients receiving boceprevir and those receiving standard therapy. The rate of a sustained virologic response was significantly greater with boceprevir plus peginterferon-ribavirin than with peginterferon-ribavirin alone among both black and nonblack patients.

The opinions expressed in this report represent the consensus of the coauthors and do not necessarily reflect the formal position of Merck or the other institutions listed as authors' affiliations.

Supported by Schering-Plough (now Merck).

Methods

Study Design

A detailed description of the study methods is provided in the Supplementary Appendix (available with the full text of this article at NEJM.org). We conducted a phase 3, international, randomized, placebo-controlled study comparing the safety and efficacy of standard therapy with peginterferon alfa-2b and ribavirin (PegIntron and Rebetol, respectively; Merck) with the safety and efficacy of two treatment regimens in which boceprevir was added after a lead-in period of treatment with peginterferon-ribavirin alone (Figure 1Figure 1Study Design.). Because of the marked difference in rates of sustained virologic response between blacks and nonblacks,7 self-identified blacks and nonblacks were enrolled separately into two cohorts.

The sponsor, patients, and study personnel were unaware of the assignment to the boceprevir or placebo group; the use of peginterferon and ribavirin was open label. The trial was conducted in accordance with the principles of Good Clinical Practice and the study protocol (including the data analysis plan; available at NEJM.org); the study design was approved by the appropriate institutional review boards and regulatory agencies. Each participant provided written informed consent before undergoing any study-related procedure. The trial was designed, managed, and analyzed by the industry authors in conjunction with the academic authors under the oversight of an independent data review advisory board. The academic authors had full access to all the data. The core writing team consisted of the principal academic author and all the industry authors, who were also responsible for the decision to submit the manuscript for publication, before which the sponsor reviewed a draft. Each author vouches for the fidelity of the trial conduct to the protocol and the completeness and accuracy of the results and data analyses.

Enrolled patients in each cohort were randomly assigned, in a 1:1:1 ratio and by means of an interactive voice-response system, to one of the three treatment groups, after stratification on the basis of the baseline HCV RNA level (≤400,000 vs. >400,000 IU per milliliter) and HCV genotype 1 subtype (1a vs. 1b). Patients in whom HCV could not be subtyped were randomly assigned to a treatment group within their HCV RNA stratum.

Selection of Patients

Eligibility criteria were a history of no previous treatment for HCV infection, age of 18 years or older, weight of 40 to 125 kg, chronic infection with HCV genotype 1, and plasma HCV RNA level of 10,000 IU per milliliter or greater. Exclusion criteria were liver disease of other cause, decompensated cirrhosis, renal insufficiency, HIV or hepatitis B infection, pregnancy or current breast-feeding, and active cancer. Liver-biopsy specimens were assigned Metavir fibrosis scores and steatosis scores by a single academic author who is a pathologist and was unaware of the assignment to the boceprevir or placebo group. The HCV genotype 1 subtype was determined with the use of the Trugene assay (Bayer Diagnostics) for purposes of randomization and by sequencing of the nonstructural 5B (NS5B) region (Virco) for subsequent analyses.

Study Regimens

Peginterferon alfa-2b was administered subcutaneously at a dose of 1.5 μg per kilogram of body weight once weekly; and weight-based oral ribavirin was administered at a total dose of 600 to 1400 mg per day in divided doses, given in the morning and evening. Treatment with boceprevir consisted of oral administration at a dose of 800 mg three times daily (to be taken with food and at an interval of 7 to 9 hours between doses) in four capsules of 200 mg each. Placebo was matched to boceprevir.

All patients received peginterferon-ribavirin during the 4-week lead-in period (Figure 1). Patients randomly assigned to group 1 (the standard of care) received peginterferon-ribavirin treatment for 44 weeks after the lead-in period, as well as thrice-daily placebo beginning at week 5. Patients randomly assigned to group 2 (response-guided therapy) received peginterferon-ribavirin plus boceprevir for a total of 24 weeks after the lead-in period; if HCV RNA levels were undetectable from week 8 through week 24, treatment was considered complete, but if HCV RNA levels were detectable at any visit from week 8 up to but not including week 24, peginterferon-ribavirin was continued, and placebo was administered, at week 28 through week 48. Patients randomly assigned to group 3 (fixed-duration therapy) received peginterferon-ribavirin plus oral boceprevir for 44 weeks after the lead-in period.

In all three groups, the study treatment was discontinued for all patients with a detectable HCV RNA level at week 24, according to a standard futility rule. Boceprevir was given for 24 weeks in group 2 and 44 weeks in group 3. All patients were followed through week 72.

Viral breakthrough was defined as achievement of an undetectable HCV RNA level and subsequent occurrence of an HCV RNA level greater than 1000 IU per milliliter. Incomplete virologic response and rebound was defined as an increase of 1 log10 IU per milliliter in the HCV RNA level from the nadir, with an HCV RNA level greater than 1000 IU per milliliter (if both samples being compared were collected the same number of days after the last peginterferon injection). In cases in which the timing between the peginterferon injection and the HCV RNA sample collection was different for the two samples, an increase of 2 log10 IU per milliliter was required to meet this criterion. If a patient had virologic breakthrough or an incomplete virologic response and rebound while receiving therapy, boceprevir treatment could be discontinued, but peginterferon-ribavirin could be continued for up to 48 weeks with appropriate clinical follow-up.

Efficacy Assessment

Plasma HCV RNA levels were measured with the use of the TaqMan 2.0 assay (Roche Diagnostics), which has lower limits of quantification and detection of 25 and 9.3 IU per milliliter, respectively; the lower limit of detection was used for decision making at various points throughout the study. HCV RNA testing was performed at the screening visit, at baseline, every 2 weeks through week 12, and at weeks 16, 20, 24, 28, 34, 40, 48, 52, 60, and 72 (depending on the treatment duration). Patients in whom study therapy was stopped because of futility were considered to have had treatment failure.

Safety Assessment

Adverse events were graded by investigators according to a modified World Health Organization grading system. Non-life-threatening hematologic adverse events were managed by means of dose reduction or administration of hematopoietic growth factors (or both). Reduction of the ribavirin dose or administration of erythropoietin was recommended when the hemoglobin level dropped to less than 10 g per deciliter, but these decisions were made at the discretion of the investigators; erythropoietin was to be stopped if the hemoglobin level rebounded to 12 g per deciliter or greater.

Statistical Analysis

The trial was designed as a superiority study to detect differences in the rates of sustained virologic response with either of the two boceprevir regimens (group 2 or group 3) as compared with standard therapy alone (group 1). The primary analyses involved all patients who had received at least one dose of any study medication; key secondary efficacy analyses were conducted for the modified intention-to-treat population, consisting of patients who completed the lead-in period of treatment and received at least one dose of boceprevir or placebo. Rates of response were determined separately (per protocol) for the nonblack cohort and the black cohort.

The protocol-specified primary efficacy end point was a sustained virologic response, defined as undetectable HCV RNA levels for 24 weeks after the completion of therapy. If HCV RNA measurements for this time point or later were missing, the 12-week post-treatment measurement was used. Relapse was defined as the occurrence of an undetectable HCV RNA level at the end of treatment but a detectable HCV RNA level at some point during the follow-up period.

Within-cohort comparisons were performed with the use of the two-sided Cochran-Mantel-Haenszel chi-square test (after adjustment for baseline stratification factors). A step-down approach was applied to hypothesis testing. Group 3 was first compared with group 1. If the resultant P value was 0.05 or less, the superiority of fixed-duration therapy including boceprevir over standard therapy would be supported, and group 2 would then be compared with group 1. If this P value was also 0.05 or less, the superiority of response-guided therapy including boceprevir over standard therapy would likewise be established.

Secondary analyses were to be conducted only if the primary comparisons showed significant differences. Formal hypothesis testing comparing the two boceprevir groups was not specified in the protocol. A multivariate logistic-regression model that included baseline characteristics and treatment group was used to identify predictors of sustained virologic response. A stepwise procedure was used to identify independent covariates, with an alpha level of 0.05 as the threshold level for variables to be entered into, and retained in, the model.

Assuming a rate of sustained virologic response of 45% in group 1 of the nonblack cohort, we calculated that 310 subjects per group would need to be enrolled for the study to have a statistical power of 90% to detect an absolute increase of 13 percentage points in the rate of sustained virologic response in group 3 as compared with group 1, with the use of a two-sided chi-square test and an alpha level of 0.05. Assuming a rate of sustained virologic response of 50% in the black cohort overall, 50 patients per group, and the use of a two-sided 95% confidence interval, we estimated that the true rate of a sustained virologic response in the black population could be estimated, within ±14%, for each of the three treatment groups.

Safety analyses included all patients who had been randomly assigned to a study group and had received at least one dose of any study medication.

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